There are a myriad of neurotransmitters and neurotransmitter receptors, each influencing a specific activity within an organism. One type of neurotransmitter receptor is the nAChR, which in humans is found throughout the nervous system in healthy individuals. The nAChR is an acetylcholine receptor that can bind to nicotine and its analogs (i.e., nicotinic agonists). The receptor is known to perform critical functions in humans and is involved in several central nervous system (CNS) disorders, including Alzheimer's disease, AIDS-associated dementia, Tourette's syndrome, cognitive dysfunction (e.g., disorders of attention, focus and concentration, such as "Attention Deficit Disorder" (ADD) and "Attention Deficit Hyperactivity Disorder" (ADHD)) and possibly Parkinson's disease; see, e.g., Halladay et al. (1997) J. Med. Chem. 40:4169-4194, U.S. Pat. No. 5,736,560 to Cosford et al., and U.S. Pat. No. 5,922,723 to Bencherif et al.
When nicotine itself is administered into the human blood stream, both central and peripheral effects of nicotine are seen such as fever, increased heart rate, trembling, nausea, increased blood pressure and convulsions, even when the drug is administered in relatively small amounts; nicotine can in fact be fatal when taken orally at doses of 250-350 mg. However, it has been suggested that certain nicotine analogs may, by contrast, be beneficial in the treatment of many diseases (Lin et al. (1994) J. Med Chem. 37:3542). That is, it has been proposed that certain nicotinic agents could modulate the nAChR as desired, but without significantly affecting those receptors that have the potential to induce undesirable side effects.
The 6-chloro-3-pyridinyl moiety has been found to confer high potency to several types of compounds acting at the nAChR, resulting in selective antinociceptive or non-opiate analgesic effects. See, for example, Badio et al. (1994) Mol. Pharmacol. 45:563-569, and Houghtling et al. (1995) Mol. Pharmacol. 48:280-287. This moiety can also confer insecticidal activity, as in the case of imidacloprid, a compound that acts selectively at the insect versus the mammalian nAChR (Kagabu et al. (1997) Rev. Toxicol. 1:75-129). ##STR1##
Surprisingly, it has been found that the N-desnitro metabolite of imidacloprid, 1-[(6-chloro-3-pyridinyl)methyl]-2-imidazolidine, is selective for the mammalian versus the insect nAChR and is similar in potency to that of (-)-nicotine (Chao et al. (1997) Pestic. Biochem. Physiol. 58:77-88).
There remains a need in the art, however, for additional compounds that modulate the nAChR, particularly the mammalian nAChR. Such compounds are useful to treat conditions, diseases and disorders that are responsive to the activity of m-nAChR modulators, including CNS disorders, pain, inflammation and inflammatory diseases, diseases caused by smooth muscle contractions, and withdrawal symptoms associated with cessation of chemical substance abuse.